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United States Department of Agriculture

Agricultural Research Service

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Research Project: DISCOVERY AND DEVELOPMENT OF NATURAL PRODUCT FOR PHARMACEUTICAL AND AGRICHEMICAL APPLICATIONS

Location: Natural Products Utilization Research

2012 Annual Report


1a.Objectives (from AD-416):
The overall goal of this project is to discover, develop and foster commercialization of new bioactive natural products as new pharamceuticals or agrichemicals and to identify, characterize and develop medicinal plants for production of pharmaceuticals as potential alternative crops.


1b.Approach (from AD-416):
The approach includes a program of: (1) Discovery of secondary metabolites from natural resources with anti-infective and anti-cancer activities based on molecular and cell-based assays [NP301, C4, PS 4B]; (2) Characterizing mechanisms of action, selectivity, toxicity and functional activity for the best candidate compounds with anti-microbial and anti-cancer properties in secondary assays and in animal models [NP301, C4, PS 4B]; and (3)Selection, agronomics and analysis of medicinally important plants and their derived products [NP301, C4, PS 4B].


3.Progress Report:
Researchers at the National Center for Natural Products Research (NCNPR) at the University of Mississippi, Oxford, MS, maintained basic discovery operations, with emphasis on the discovery of antifungals, anticancer, anti-inflammatory agents and immunomodulating agents. University scientists continued to source plant materials for screening from our own plant collections and from numerous collaborators. Added 700 plant samples to our inventory this year. Screened over 4,000 natural product crude extracts, semi-purified fractions and purified compounds for biological activities against specific molecular targets and whole cell systems. As part of our continuing effort in the search for anti-infective, anticancer, and immunomodulator/anti-inflammatory leads from natural sources, more than 130 compounds (including 13 new natural products) were identified from plants, marine sponges, and fungi. Many showed potent phytotoxic, antifungal, antibacterial, or antimalarial activities. Over 800 of our isolated actives or extracts have been characterized in more detailed follow-up assays to determine their mode of action, pharmaceutical properties, toxicity, and selectivity across a range of assays. In addition to these basic operations we have selected a number of these compounds for more advanced study, whether for characterizing mechanisms of action, determining suitability for further pharmaceutical development, evaluation in disease models in preclinical studies, or in field applications. In collaboration with ElSohly Laboratories, Inc., continued development of lead compounds shown to be effective in animal models for desensitization to poison ivy dermatitis. Two leads in the poison ivy project are now undergoing formulation development, and bioavailability and toxicology studies. Construction of new facilities of the Medicinal Plant Garden at the University of Mississippi was completed this year, and work has begun to develop the outdoor growing sites. Completed facilities include a laboratory building, horticulture building, greenhouse, shade house, and equipment building. These facilities will enhance the capabilities of NCNPR to cultivate and process medicinal plants to be used in the discovery program. NCNPR continued planning a major construction project this year to complete its major research building with a 90,000 sq. ft. research wing. Construction documents were reviewed and approved by the funding agencies (Health Resources and Services Administration; National Institutes of Health) and a construction contract has been awarded for the project which will be completed in March, 2014. The new research wing will expand and enhance the research capabilities of NCNPR with a second plant specimen repository, herbarium, and laboratories for plant tissue cultures, cellular cultures, scale-up isolation and synthetic chemistry.


4.Accomplishments
1. Develop antifungal natural products. Because many organisms contain inherent protective mechanisms the natural environment is a rich source for compounds to treat fungal diseases. Scientists at the National Center for Natural Products Research (NCNPR) at the University of Mississippi in Oxford, MS, aim to discover novel antifungal compounds for treating life-threatening opportunistic fungal infections. This ongoing program covers various aspects of drug discovery including screening and isolation of natural product antifungal compounds, determining their mechanism of action, and understanding potential resistance mechanisms. In this past year, over 4,000 natural product samples were screened for antifungal activity against 5 different fungal pathogens, and over 50 “hits” were identified. The mechanism of action of 8 antifungal compounds was analyzed by genomic and genetic approaches, and 2 potentially novel antifungal pathways were identified. Several important achievements have resulted in the past year including: (a) the isolation and identification of new antifungal compounds, and (b) the identification of new molecular pathways (heme synthesis and fatty acid metabolism) targeted by two different antifungal compounds. These pathways are new in that they are not targeted by current antifungal drugs used clinically. These accomplishments may lead to new treatments for numerous diseases of plants, animals, and humans.

2. Develop agents for prevention/treatment of poison ivy dermatitis. Poison ivy is a widespread plant that causes an itching rash in most people who touch it. Scientists at the National Center for Natural Products Research (NCNPR) at the University of Mississippi in Oxford, MS, are developing preventive treatments for poison ivy dermititus. Two lead compounds shown to be effective in animal models for desensitization to poison ivy dermatitis are now undergoing bioavailability and toxicology studies expected to be completed in August, 2012. These compounds are also now undergoing formulation development studies. A batch of pharmaceutical-grade ingredient of one of the lead compounds has been manufactured in anticipation of upcoming clinical studies. These accomplishments may lead to new products for a common but serious condition.

3. Develop treatments for cancer. A cancer research program requires a drug discovery program in order to explore all avenues of treatment. Scientists at the National Center for Natural Products Research (NCNPR) at the University of Mississippi in Oxford, MS, operate the Drug Discovery Core of the University of Mississippi Medical Center (UMMC) Cancer Institute. Because the NCNPR core group accelerated the development of screening assays that target signal-transduction pathways known to be involved in the expression of cancers, this new screening program is one year ahead of its original development plan. Over 500 crude plant extracts and 50 pure compounds have now been screened for anticancer activity. The most promising anticancer compounds will be produced in quantities required for further development and evaluation by the UMMC Cancer Institute, which may lead to new treatments for cancer.

4. Discovery of new drugs to prevent or treat diseases caused by protozoans. New drugs for malaria and leishmaniasis will reduce risk of treatment failure, reduce risk of developing resistance, and reduce side-effects of the drug now commonly used. This year scientists at the National Center for Natural Products Research (NCNPR) at the University of Mississippi in Oxford, MS, screened hundreds of natural products and synthetic analogs of natural products for activity against malarial and leishmaniasis. A number of novel anti-protozoal compounds were discovered. These accomplishments contribute to efforts to fight these widespread diseases.


Review Publications
Dai, L., Jacob, M.R., Khan, S.I., Khan, I.A., Clark, A.M., Li, X. 2011. Synthesis and antifungal activity of natural product-based 6-alkyl-2 3 4 5-tetrahydropyridines. Journal of Natural Products. 74(9):2023-2026.

Avula, B., Wang, Y., Khan, I.A. 2012. Quantitative determination of curcuminoids from the Roots of Curcuma longa, Curcuma species and dietary supplements using an UPLC-UV-MS method. Journal of Chromatography. 3(1):1-6.

Wang, M., Avula, B., Parcher, J.F., Khan, I.A. 2011. Comparison of concentration pulse and tracer pulse chromatography: experimental determination of eluent uptake by bridged-ethylene hybrid ultra high performance liquid chromatography packings. Journal of Chromatography A. 1220:75-81.

Wang, Y., Avula, B., Fu, X., Khan, I.A. 2012. Simultaneous determination of the absolute configuration of twelve monosaccharide enantiomers from natural products in a single injection by UPLC-UV/MS method. Planta Medica. 78:834-837.

Khan, S.I., Aumsuwan, P., Khan, I.A., Walker, L.A., Dasmahapatra, A.K. 2011. Epigenetic events associated with breast cancer and their prevention by dietary components targeting the epigenome. Chemical Research in Toxicology. 25:61-73.

Raman, V., Avula, B., Galal, A.M., Wang, Y., Khan, I. 2012. Microscopic and UPLC-UV-MS analyses of authentic and commercial yohimbe (Pausinystalia johimbe) bark samples. Journal of Natural Medicine. 249-252.

Avula, B., Wang, Y., Ali, Z., Smillie, T.J., Khan, I.A. 2011. Quantitative determination of triperpene saponins and alkenated-phenolics from Labisia pumila using LC-UV/ELSD method and confirmation by LC-ESI-TOF. Planta Medica. 77:1742-1748.

Avula, B., Wang, Y., Moraes, R.M., Khan, I.A. 2011. Rapid analysis of lignans from leaves of Podophyllum peltatum l. samples using UPLC-UV-MS. Biomedical Chromatography. 25:1230-1236.

Avula, B., Shukla, Y.J., Wang, Y., Khan, I.A. 2011. Chemical fingerprint analysis and quantitative determination of pregnanes from aerial parts of caralluma species using HPLC-UV and identification by LC-ESI-TOF. Official Methods of Analysis of AOAC International. 94(5):1383-1390.

Xu, W., Li, X. 2011. Antifungal compounds from Piper species. Current Bioactive Compounds. 7(4):262-267.

Huang, Z., Chen, K., Xu, T., Zhang, J., Li, Y., Li, W., Agarwal, A.K., Clark, A.M., Phillips, J.D., Pan, X. 2011. Sampangine inhibits heme biosynthesis in both yeast and human. Eukaryotic Cell. 10(11):1536-1544.

Agarwal, A.K., Tripathi, S.K., Xu, T., Jacob, M.R., Li, X., Clark, A.M. 2012. Exploring the molecular basis of antifungal synergies using genome-wide approaches. Frontiers in Microbiology. (3)15:1-6.

Zhang, X., Jacob, M.R., Rao, R.R., Wang, Y., Agarwal, A.K., Newman, D.J., Khan, I.A., Clark, A.M., Li, X. 2012. Antifungal cyclic peptides from the marine sponge Microscleroderma herdmani. Journal of Medicinal Chemistry. 2:7-14.

Zhang, J., Rahman, A.A., Jain, S., Jacob, M.R., Khan, S.I., Tekwani, B.L., Muhammad, L. 2012. Antimicrobial and antiparastic abietane diterpenoids from Cupressus sempervirens. Research and Reports in Medicinal Chemistry. 2:1-6.

Last Modified: 4/20/2014
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